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An Update from Geoffrey Guy


Pubdate: Wed, 16 Jul 2003
Source: Anderson Valley Advertiser (CA)
Column: Cannabinotes
Copyright: 2003 Anderson Valley Advertiser
Contact: ava@pacific.net
Author: Fred Gardner
Cited: G.W. Pharmaceuticals http://www.gwpharm.com/
International Cannabinoid Research Society http://cannabinoidsociety.org/
Bookmarks: http://www.mapinc.org/mmj.htm (Cannabis - Medicinal)
http://www.mapinc.org/find?323 (GW Pharmaceuticals)

AN UPDATE FROM GEOFFREY GUY

Geoffrey W. Guy, MD, is a successful British pharmaceutical entrepreneur who in 1998 founded a company, G.W. Pharmaceuticals, to produce and market medically useful extracts from the cannabis plant. Guy, now 50, had never used cannabis himself; his interest had been piqued by British multiple sclerosis patients asserting that marijuana eased their painful spasms.

Guy's business plan was straightforward: grow plants under controlled conditions in which various cannabinoids of interest (THC, CBD, and several others) predominate. Then blend uniform, pharmaceutical-grade extracts containing different cannabinoid ratios and provide them to investigators for use in clinical trials. To date GW has successfully tested three extracts -high-THC (which GW has dubbed "Tetranabinex"), high-CBD ("Nabidiolex"), and a 50-50 mix ("Sativex").

This spring, right on schedule, GW filed its "research dossier" with the Medicines and Healthcare Products Regulatory Agency (the British equivalent of the FDA). It included data on successful clinical trials involving chronic pain patients and MS and spinal-cord-injury patients.

Soon after filing the application, GW signed a deal allowing Bayer AG to market one of its extracts in the UK under the Sativex(r) brand. Bayer also optioned marketing rights in Europe, New Zealand, and Canada. GW gets cash to spend on research, production, and clinical trials plus a cut of future sales proceeds. Bayer is betting that the MHRA will approve Sativex or return the application dossier to GW with readily-met requirements. A decision is expected by the end of the year.

This interview was conducted at the NAV Conference Center in Cornwall, Ontario, 6/29/03, at the end of the International Cannabinoid Research Society's 13th annual meeting. Two papers and a poster had described successful trials of GW extracts.

C'Notes: How large is the GW workforce?

GWG: We have about 130 employees, but we subcontract a lot of work. So the overall program in full-time equivalents is higher than 140. Last year we engaged our first contract grower, a major commercial grower who grows food for supermarkets at enormous scale. Their glasshouses dwarf ours.

C'Notes: How much are you producing?

GWG: At present we are producing between 50 and 60 tons, wet weight. We are licensed to produce 100 tons, which we will be doing within the next year. That's 10 tons or more of dried, herbal cannabis.

C'Notes: Could you describe the basic cultivation cycle?

GWG: We take cuttings and place them in a growing medium. They root very nicely -we get about a 95+% rate on our cuttings. One operative during the day can take 2,000 cuttings... At the end of two weeks the plant is potted up into an organic compost-type growing medium that we alter to provide optimum aeration. The pots are lined up on very large trays, each tray contains about 200 plants. They're on rails so they can move down the line. Every week the process is the same. So as you look down the glasshouses, you see, stepwise, week-by-week, one week's worth of growth, the next week's worth of growth, and so on, exactly the same... Starting with cuttings on one side of the production line, ending with ready-to-harvest on the other side.

C'Notes: How tall are they at harvest?

GWG: They're roughly one meter high. We've done quite a lot of research on optimal morphology. Our objective is to produce the maximum amount of consistent cannabinoid material per growth cycle. We have six cycles per year, so we grow for a short maturation period.

Typically, the THC plants are more bushy, 100-150 flowering heads, whereas the CBD variety is more of a bottle-brush variety, a little bit taller. So we plant our CBD variety at a greater density than the THC variety. If it's too dense, of course, the leaves don't get enough airflow, humidity can build up under the canopy, you can't work with them. And if they're too tall they'll stop light falling on other plants. So density has been worked out for optimal air and light... The cuttings are always taken to provide us a special shape. We always procure a single apical bud so we don't get branched or abnormally shaped buds. The technique we use now gives us a very consistent shape and output. The shape of the plant is determined by the shape of the cutting.

There's no pruning... We wanted to have a standardized, automated process. We've basically produced what is a fabrication dossier for growing a cannabis plant. If one pharmaceutical company develops a synthetic molecule, and they want it to be made by another company, they produce a fabrication document. We did that. And when we transferred the technology to our contractor last year, the very first crop they produced came within the specifications. Their plant looked slightly different, and we've tuned in on the reasons and they have better control now.

C'Notes: What pests have you encountered and what do you do about them?

GWG: There are only two, really: thrips and red spider mites, both of which we control with friendly mites. We don't spray at all. Thrips on the whole are not an economical problem unless they get out of hand. When we've brought in cannabis materials from other places, the spider mite burden has been enormous, so we have a quarantine situation where nothing comes in from outside unless it's been isolated. The red spider mite is the one that, if we see it, we immediately remove plants. We'll have no hesitation in removing that whole week's worth of material from the cycle. As it is, we tend to identify sickly plants, and we've really kept things under control.

The only other mite we had was a Chinese bamboo mite. We use bamboo canes to keep the plants upright. and the mites came with the canes.

C'NOTES; Is extraction the next step?

GWG: Next comes drying -each strain is dried separately. Then extraction, by means of ethanol. Waxes remain in the crude extract, which have to be removed in a separate step. Then we take those two crude extracts and we formulate them together to achieve precisely the desired ratio... I took the view that the way to arrive at a very consistent product is exactly the way that burgundy winemakers produce Burgundy -they blend to a standard based on a previous great year.

When I made this decision, I wasn't able to know how precise the plant is. We've been really quite shocked at how precise the plant is in producing the same cannabinoid ratios, provided the genetics are the same. So, in the early days, the decision was made to grow plants that are rich in one cannabinoid or the other, extract and concentrate the components. Quality-control procedures enable us to determine the exact composition of the extracts, and we blend them to give us an absolute final ratio that meets our specifications.

With these two preparations you can produce all the ratios in between instead of having to grow a new plant for each blend. In dossiers (for government approval in the UK and elsewhere) we supply extensive information on the consistency and quality, the toxicology and pharmacology of each extract. They're then brought together in the manufacturing process, and at that point we generate the clinical data.

C'Notes: what percentage of the plant do the cannabinoids account for?

GWG: That would depend on the variety and the subvariety. We find that for optimum growth and optimum use,12 to 15% is the comfortable range. Bear in mind that's the leaf as well as the bud. It's not the content of a manicured bud. We could produce plants with far higher cannabinoid content, but they're not as reliable, they become extremely sticky, they're difficult to handle, they're more prone to bugs...

C'Notes: And what percentage of the cannabinoids in your high-THC strain is THC?

GWG: 97%.

C'Notes: What's the level in your high-CBD strain?

GWG: Near 95% of the cannabinoid content is CBD. The rest is THC and some minor cannabinoids; the variation is minute. The plant is producing these materials at a level of purity that you wouldn't find in the first 10 or 12 steps of a synthetic process. Plus, it's stereospecific, it produces the correct isomer.

C'Notes: When researchers at this (ICRS) conference thank GW Pharmaceuticals for providing the CBD used in their studies, are they talking about pure CBD or your high-CBD extract?

GWG: It depends on what they requested and how early they asked us. We had to produce internal standards. We found that the existing standard for THC wasn't accurate enough... We have now produced highly purified internal standards for all our analytical equipment. These reference standards are 99.9 percent pure and we've done that for most of our leading cannabinoids: THC, CBD, THC-V, CBC, CBD-V, CBG and CBN.

A researcher can specify whether they want pure CBD, pure THC, pure CBC, pure CBG, or 98% pure, 97%, 95%, or the actual extract -the two components. It's the extract that's eventually going to be the medicine, so the pharmacology we want to look at is the extract. But we appreciate that there are a lot of laboratory in vitro systems that can only discern anything when exposed to single molecules. As soon as you put more than one molecule into the system, you just get a gray scale of results. The extracts are interesting to us, because that's what patients take; but we're also happy to provide either fractions of the extracts or purified components of the extracts.

C'Notes: Are you conducting additional clinical trials while awaiting government approval?

GWG: The trials program so far has mainly covered patients with neuropathic pain and neuropathic disfunction. We are conducting five more trials in those areas... We are conducting a trial involving 130 or 140 patients with cancer pain. These are very difficult trials to run because the patients have to have an advanced-stage cancer requiring regular opiate therapy, but not so advanced that they can't participate in the trial, and their condition has to remain stable for at least the two weeks of the trial. Recruitment for such studies is always difficult but we've done very well. We're running a study in the UK and countries in Europe as well. We are awaiting results by the end of the year.

Some of the results of our clinical trials have now been been published in peer-reviewed publications. Peer-review publication of clinical-trial results tends to take longer than publication of pre-clinical work. Analyzing a clinical trial requires an army of people. We have a clinical department of 45 people that organize and monitor our clinical trials. Every piece of data has to be checked. It's a massive undertaking. Even a small clinical trial involving a few dozen patients requires a lot of checking up. And if any of the data items are missing, or fall outside normal ranges or fall outside acceptable ranges, our monitor has to visit the site and confirm or find the correct number and revise accordingly. This is pharmaceutical requirement. This is Good Clinical Practice. You have to ensure that your data set is absolutely right.

The data is entered into our databases by a double-entry system to catch any inaccuracies. Then, for each trial, we create a trial-specific database with all the relevant information. Because these trials are early-stage, we're collecting a lot more information than we would in later stage trials that are looking into specific endpoints. Safety is everything in these trials. The real judge of whether a product will be approved is safety first, efficacy second.

C'Notes: Have any red lights flashed with respect to safety?

GWG: No, what has been said about the safety of cannabis in journals, what has been said about the therapeutic index, it's all been borne out in our trials. We're very pleased, of course, and it's a major part in our presentations, because it's so striking.

C'Notes: Will your label warn of side effects?

GWG: The label for our product -subject to approval by the authorities-will probably mention "mild intoxication," which is transient and occurs during the titration phase.

In our clinical trials, patients are invited to explore the optimal dose and it's really not a problem on an ongoing basis, it doesn't interfere with day-to-day living. We certainly can differentiate between beneficial effects and psychoactive effects. There are some patients who do have some problems, who continue to seek benefit when they're moving into levels that cause intoxication. Some of these patients can alter their daily living around that. We'll probably deal with them by offering different ratios and different delivery modalities in due course.

The second issue is dry mouth.

The third issue is some nausea because of the taste of the material.

Our label may also contain a warning about vasovagal episodes [light-headedness, dizziness, fainting]. Some patients who are very sensitive and take too high a dose may experience a fainting episode with tachycardia [rapid heartbeat]. But all of these are well known from the vernacular reports. We had a concern early on that people going out of their way to use illicit materials might tend to under-report adverse effects, so there might be some information about cannabis that had been concealed. Our methodology was designed to pick up and report every adverse effect, whether or not it's related to the drug. So my question was, would we begin to see some side-effect profiles that had not been recognized heretofore? We really haven't. We had a few patients who reported panic. We found that the easiest thing to do is to advise the patient what they might feel, and that if they did, in their titration phase, overdose a little bit, we advised them to sit down, relax, and not fight it.

We've become more careful in the initial titration. Early on in the phase-2 studies we were finding MS or spinal-cord injury patients who'd had marked intractable symptoms which were refractory and resistant to all other therapies -pain, for example-that were markedly relieved or, in some notable cases, disappeared by lunchtime on the first day of treatment. So I think we became gung ho until we encountered some patients who were exquisitively sensitive. And then we introduced a regimen that allowed us to accommodate all levels of sensitivity -which means that nobody's going to get a lot of symptom relief on the first day.

We now increase dosage by slight increments over a two or three day period. Once they've finished that, they're onto free titration. Free titration has been very helpful. In North America people think of titration as the amount the patient takes -how much. What is more important is the rate of change of blood levels. The quicker the rate of change in blood levels, the more likely you are to get a psychoactive effect. The slower you trickle the drug in, the higher the levels you can achieve without psychoactive effect. The risk is, bypassing the very innocuous, un-damaging intoxicating effects, the patient can be exposed to the vasovagal effects. We actually find in the titration process that the very mild progress of intoxication -and we have to be very careful when we use this word, we're talking about very low levels, levels that would be disappointing to a recreational user- as soon as the patients get that signal, they know that they're already at a satisfactory therapeutic level. That's what we postulated five years ago and that's clearly what happened.

What is most important for patients to get into that therapeutic window is to be able to alter the dosage. Some of our patients will take their medicine three times a day, morning, noon and evening. Some will just take it in the evening. But some find it best to just take small doses often during the day -maintaining their blood levels, topping off, if you will, so they don't experience peaks and troughs.

C'Notes: In the study by Steven McKerral [describing the use of GW extracts in the treatment of pain stemming from nerves being torn away from the spinal cord] somebody dropped out because of a side effect called "disguesia," which was a new one to me. Does your product taste disgusting? And how serious a problem is that going to be?

GWG: The cannabinoids, we understand from our patients -especially if they're not used to cannabis-have a really quite strong taste. Some people find the taste not very pleasant. But that's true of many drugs. With a drug that's delivered by a spray under the tongue, which is a very sensitive area, the issue is magnified. Some patients reported a stinging sensation. We're now advising patients that it can be sprayed anywhere in the mouth.

C'Notes: Aren't there food chemists who specialize in making things taste better?

GWG: We've given it a peppermint flavor and we have all sorts of flavorings to look at. But you'd be surprised, trying to solve taste issues can delay a drug development program by two or three years. I took the view that, in the political climate in which we first started, producing a sweet-tasting, very pleasant drug would not help us win approval. So it wasn't high on our agenda. And it really isn't a major problem... I think that patient was the only one who dropped out (of a GW study).

As I told you a few years ago, we chose this formulation because it's not exotic. There are so many hurdles to overcome in taking cannabis through the approval process... We're developing a product that is not the norm in the modern pharmaceutical industry. So I wanted to keep all other issues and potential problems to a minimum. That's why we chose a straightforward dosage form, an ethanolic-based formulation. You have to apply a lot of technology to keep it stable, and the stabilizers have been a challenge, but we've got there now... Behind the first product we have a whole range of line extensions -new, improved formulations, and those will address each of these other issues. In the UK, the social, moral and medical imperative in the UK -and the political imperative-was to obtain approval for a product as soon as possible. And that does not allow one the luxury of thinking 'Does it taste nice or not?' But that will certainly be addressed...

Formulation and application are side issues. The main point is, the side effects listed on our label are those you might see on the mildest over-the-counter medicines. If you consider that patients with MS are taking drugs with marked side effects, drugs that can damage the liver, the pancreas, the kidneys.... Opiates that in acute overdose can induce respiratory failure and death... In comparison, the side-effect profile for our materials is absolutely excellent.

One has to look at what happens in patients and how well they tolerate the medicine. Whatever the side-effects of cannabis, they are minor compared to the side effects of medicines patients are currently taking. The risk-benefit equation is everything to the patients.

C'Notes: What else can you say about your research pipeline?

GWG: There will be another wave of studies. We are particularly interested in the effects of cannabinoids in response to inflammation. We're not simply talking about the cannabinoids as an anti-inflammatory in the classical sense, like a non-steroidal. We'reinterested in the mechanism of action and the effect of different cannabinoid ratios... We have a phase II study in rheumatoid arthritis running at the moment. The beneficial modifying effects of CBD are very clearly seen in our arthritis program... We are moving on into inflammatory bowel, where what we know about antispasmodic effects will be applicable... We are interested in malnutrition issues. Senile anorexia. Issues of air hunger (sleep apnea, for example). I'd like to move on to epilepsy fairly soon; that's the one area where I wish we'd made more progress... We're working with a group in Brazil to look at schizophrenia and bipolar disorder.

The important thing is not to have six or seven different indications one-third completed at this stage; the important thing is to have our product approved. And that's where we've focused. The dossier is in and running. We've recently signed the agreement with Bayer for the UK, and they have an option for Europe, Canada and New Zealand. The rewards of that are, the company has been able to sustain itself. Friday in London we announced that we'd raised 20 million pounds for the R&D program. So to date my fundraising is up to 100 million US Dollars -a very significant research war chest.

We've just completed a small trial on glaucoma. Our interest in glaucoma is not strictly to drop the pressure. We're looking at the neuroprotective effects on the retina...

The cannabinoids seem to be inhibiting angiogenesis in tumors, but possibly promoting angiogenesis in damaged nerve cells. They are modulators. If some level is too high the cannabinoids take it down, if something is too low they pick it up. That's why the effect of cannabinoids depend on the status of the receptor, the health status of the patient, and the extent to which receptor recruitment or redundant systems are compensated.

C'Notes: Please explain for the layman (c'est moi).

GWG: Two patients may have the same symptom. One may have just started to use compensating mechanisms. The other may be at the point where the compensating mechanisms are giving way to decompensating mechanisms. To determine the effect of the cannabinoids, one has to take into account, "What is the position when the cannabinoids reach that system?" We have to build a bridge between some of the in vitro systems which don't take into account the in vivo feedback...

C'Notes: So much seems to have gone according to plan. What has surprised you?

GWG: A lot of observers were prepared to see trials that might show that yes, cannabis medicines do have a medical effect, and therefore one could make the case that they deserve a place in the medical armamentareum... What we're showing is much more dramatic than that. Cannabis medicines have enormous pharmacological capabilities. There are a myriad systems that they modulate. They have a unique capability to address, in a disease like multiple sclerosis, a whole range of symptoms. Heretofore, each patient has had at least one drug per symptom, and sometimes more than one, and then a host of drugs to take care of the side effects of those drugs. We're seeing that cannabis medicines can address a wide range of symptoms with incredibly low side effects. And what is in prospect -David Bacon has reported that cannabinoids are almost able to arrest the progression of MS in his animal models. That would be startling.

I think we're just about to move into a very interesting period. You've seen the tone of this meeting. Five years ago, presenter after presenter would describe their work and sit down with nobody really making a link between them. The innuendo was that each of thee mechanisms might in some way be contributing to some terrible, nasty effect of cannabis. Five years ago you'd see studies that didn't use any cannabis -that used synthetic cannabinoids with ingredients that weren't in the cannabis plant- and the results were used to say something (bad) about cannabis. That seems to have stopped. Five years ago the tide was going against therapy. The "therapeutic potential" speakers at our first meeting in Montpelier were sort of tolerated. This year I really felt for the first time that I was at a meeting describing the basic science around a number of therapeutic opportunities. The papers are now talking about the science as it may relate to therapy. And the audience is almost entirely focused on beneficial effects.

At one of the question sessions (at the ICRS meeting) somebody said, "there's no report in the literature..." What that actually means is, "there's no report in the literature that they've read!" But there's plenty of good stuff in the literature. In four and a half years, we've made good progress.

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